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Journal Article
A day in the life of the spliceosome
2014
Overview
Key Points
Spliceosomal snRNAs are transcribed from specialized promoters, which recruit RNA polymerase II cofactors that aid in proper 3′ end maturation of these non-polyadenylated transcripts.
Like most non-coding RNAs, small nuclear RNAs (snRNAs) use cognate antisense elements to interact with their nucleic acid targets via base pairing.
Assembly of functional small nuclear ribonucleoproteins (snRNPs) involves a series of non-functional intermediates that are often sequestered in subcellular compartments that are distinct from their sites of action.
snRNP function requires multiple protein partners (such as DExD/H helicases or WD box proteins) the roles of which may include modulating RNA structure or tethering an enzyme.
snRNPs recognize specific sequences in pre-mRNAs and assemble into the spliceosome in a stepwise manner. The splicing reaction itself is catalysed by U6/U2 snRNA complex that resembles a self-splicing ribozyme.
Alternative splicing is typically regulated by multiple
cis
-elements and
trans
-factors, which form complex interaction networks that may provide a great deal of regulatory plasticity.
Pre-mRNA splicing can be regulated throughout the entire spliceosomal assembly pathway, although the early steps are the main stages of regulation.
The tight regulation of each step of spliceosome assembly from small nuclear RNAs and associated proteins requires coordination between distinct cellular compartments. This in turn dictates where and when alternative splicing occurs and is vital for normal gene expression control.
One of the most amazing findings in molecular biology was the discovery that eukaryotic genes are discontinuous, with coding DNA being interrupted by stretches of non-coding sequence. The subsequent realization that the intervening regions are removed from pre-mRNA transcripts via the activity of a common set of small nuclear RNAs (snRNAs), which assemble together with associated proteins into a complex known as the spliceosome, was equally surprising. How do cells coordinate the assembly of this molecular machine? And how does the spliceosome accurately recognize exons and introns to carry out the splicing reaction? Insights into these questions have been gained by studying the life cycle of spliceosomal snRNAs from their transcription, nuclear export and re-import to their dynamic assembly into the spliceosome. This assembly process can also affect the regulation of alternative splicing and has implications for human disease.
Publisher
Nature Publishing Group UK,Nature Publishing Group
